Implant

ABSTRACT

The present invention relates to an implant for use in the human body, an implant substrate being coated with a material which contains chemical compounds between one or more metals (M) of group IV A of the periodic system, nitrogen (N) and oxygen (O), 2 to 45% of the volume in the coating material being formed by voids whose sizes range from (0.4 nm) 3  to (50 nm) 3 , and the remaining volume having a composition of a metal of group IV A of the periodic system to nitrogen to oxygen of 1:(0.1 to 1.7):(0.1 to 1.7), a material having formula MN x  O y  (wherein x,y=0.1-1.7) resulting. 
     The invention also relates to the use of this implant for implantation into the animal or human body.

The present application is a U.S. nationalization pursuant to 35 U.S.C.371 of PCT/DE96/00322 filed on Feb. 22, 1996 which is in turn based onGerman Patent Application No. 195 06 188.8 filed on Feb. 22, 1995.

This invention relates to implants.

Various artificial materials are introduced into the human body as ashort-term or relatively long-term implant for diagnosis and treatment(catheters, probes, sensors, stents, artificial heart valves,endotracheal tubes etc.). The selection of the material for theseimplants depends on the stability and geometry required to insure acertain function of the implant. In order to meet these functionaldemands, it is often not possible to pay sufficient regard to the factof whether these materials are biocompatible. Therefore, it is useful toimprove the materials from which these implants are made by coatingswhich are compatible with blood and tissue. Coatings are required whichactivate the coagulation system only to a minor degree, and which causefew endogenous defense reactions thus reducing the deposit of thrombiand biofilm on the implant surface. A coating is useful for allmaterials which are directly introduced into the bloodstream, e.g. forvascular prostheses, stents, artificial heart valves, as well as forimplants which are in contact with tissue, e.g. cardiac pacemakers ordefibrillators and for implants which are in contact with body fluids,e.g. bile duct drains, catheters for draining urea and cerebrospinalfluid, and endotracheal resuscitation tubes. The blood compatibility ofimplants is influenced decisively by their surface properties. In orderto avoid the formation of thrombi ("antithrombogeneity"), relativesmoothness is necessary to prevent the deposit and destruction, ofcorpuscular components of the blood and activation of the coagulationsystem. In addition, direct charge exchange processes must be preventedbetween coagulation-specific proteins and the implant surface.

It is known to use coatings made of pyrolytic carbon as a commonmaterial for heart valves to meet these demands. In addition, it isknown to use semi-conducting materials, e.g. a-SiC:H as an implantcoating, to prevent the charge exchange processes between thecoagulation-specific proteins and the implant surface (A. Bolz, M.Schaldach, "Haemocompatibility optimisation of implants by hybridstructuring", Med. & Biol. & Comput., 1993, 31, pp. 123-130).Furthermore, it is known to employ Ti₆ Al₄ V as a coating (I. Dion, C.Baquey, J.- R. Monties, P. Havlik, "Haemocompatibility of Ti₆ Al₄ Valloy", Biomaterials, Vol. 4, 1993, pp. 122-126). A plurality ofplastics have also been investigated in the field of polymer chemistryto produce non-adhering surfaces. In this field as well, the problem hasnot yet been solved satisfactorily (R. F. Brady Jr., "Coming to anunsticky end", Nature, Vol. 368, 1994, pp. 16-17).

Although implants having a carbon coating and a porous structure meetthe demands made on the surface properties, they have the drawback thatan electron transfer caused by tunneling of occupied, valence band-likestates of the protein to free states of the solid leads to cleavage offibrinogen in the blood. The resulting fibrin monomers polymerize andproduce an irreversible thrombus. Although implants made of rutileceramics prevent these charge exchange processes, they were not readyfor series production because of the high production costs. Althoughimplants having a coating made of amorphous carbon (a-SiC:H) can beproduced in a cost-effective fashion, the drawback of this materialconsists in that it is not hard enough for certain applications. Thismaterial is presently produced by means of CVD methods which requiregreat heating of the substrate as an additional problem, so thatapplication is made more difficult for a large number of heat-sensitivebasic materials. In addition, this material has a fixed band gap and lowconductivity. Both properties lead to the formation of thrombi ratherthan preventing them.

Therefore, it is the object of the present invention to provide animplant of the above-mentioned kind with a surface by which theactivation of blood coagulation accompanied by the formation of thrombias well as the formation of a biofilm are reduced significantly.

The object is achieved by an implant according to the present invention.

An implant within the meaning of this invention shall comprise everydevice or every means which can be implanted into an animal or humanbody or inserted therein on a relatively long-term basis and short-termbasis, respectively, or be attached to the animal or human body. Thefollowing examples are mentioned: catheters, probes, sensors, stents,artificial heart valves, endotracheal tubes, cardiac pacemakers.

The material for coating the implant, i.e. the coating material,contains the following chemical compounds: one or more metals of the IVAgroup of the periodic table, nitrogen and oxygen. 2-45%, preferably10-43%, more preferably 20-35%, of the volume is formed by voids whosesizes range from (0.4 nm)³ [=0.064 nm³ ] to (50 nm)³ [≈125000 nm³ ],preferably (0.4 nm)³ to (20 nm)³. The gaps frequently described in theliterature (e.g. John A. Thornton, The microstructure ofsputter-deposited coatings, J. Vac. Sci. Technol. A4 (6), 1986, pp.3059-3065) and formed by columnar film growth are not meant to be withinthe scope of these voids. Thus, it is not the known gaps between thecolumns that are of concern but rather voids within these columns. Thesevery voids result in the properties specific to the invention. Theremaining volume of the coating material (98-55%, preferably 90-57%,especially preferably 80-65%) has a composition of a metal of group IVAof the periodic table to nitrogen to oxygen such as 1:(0.1 to 1.7):(0.1to 1.7), preferably 1:(0.4 to 1.2):(0.1 to 1.2). The formula of thematerial is MN_(x) O_(y), "M" being a metal of group IVA of the periodictable and x and y, respectively, being values from 0.1 to 1.7. The aboveratios refer to the particle number and molar ratios, respectively. Themetal of group IVA of the periodic table may be titanium, zirconium orhafnium or a mixture of two or the three metals. Preferably, it istitanium.

As far as the sizes of the voids are concerned, it is preferred thatthey occur in the lower range, i.e. that they are preferably not greaterthan (15 nm)³. The "remaining volume" of the material preferablycomprises one or more chemical compounds selected from the groupconsisting of MN_(x) (x=0.7 to 1.2), MO_(x) (x=0.7 to 1.2), Magnelliphases of the M--O system (MnO_(2n-1)), MO₂, M₂ N (wherein M=metal ofgroup IVA of the periodic system) as well as about 0-30%, preferably0.5-5%, of carbon compounds of a metal of group IVA of the periodictable. By the addition of these carbon compounds the spectrum ofpossible uses of the coating is extended and the stability is increased,which has been shown e.g. in the case of urine catheters. Minor amountsof titanium carbides as impurities are usually not disturbing, they evenpermit a cheaper production of the coating. The possibility that thechemical phases may preferably be present in the coating material incrystalline or amorphous form, prevents the apposition and destructionof corpuscular components of the blood, so that the involved activationof the coagulation system is prevented. Therefore, the coating materialcounteracts the formation of thrombi, i.e. shows "antithrombogenic"properties.

The possibility of introducing a fractual size distribution of thevoids, permits an essential extension of the surface as used e.g. forpacemaker electrodes. A greater surface permits a reduction of theelectrical impedance and thus a longer service life of a pacemakerbattery.

Furthermore, the coating material preferably includes that the real partof the refractive index for the X-ray wavelength of 0.0709 nm rangesfrom 0.9999984 to 0.9999973. The mass density of the coating materialpreferably ranges from 3.5 to 5.4 g/cm³, preferably from 3.7 to 4.5g/cm³, more preferably from 3.8 to 4.2 g/cm³.

In addition to the metals of group IVA of the periodic table, thecoating material may also contain niobium, tantalum, tungsten,molybdenum or alloys thereof as additional metals, which improves thecorrosion resistance of the coating.

When the material contains hydrogen (dissolved or preferably in boundform), free bonds are saturated in the amorphous phases. This affectsthe electron state distribution which is more favorable forbiocompatibility.

The thickness of the coating ranges preferably from 3 nm to 3 mm, morepreferably from 10 nm to 2 mm, most preferably from 30 to 71 nm.

The coating preferably has a specific resistance ranging from 30 to30000 μΩ.cm, preferably 100 to 6000 μΩ.cm, more preferably 2000 to 3000μΩ.cm. The specific resistance can be adjusted without any problem bythe selection of the void fraction or portion. The specific resistanceof the material increases when voids are added. For example, thespecific resistance of TiN₀.98 O₀.2 may be 70 μΩ.cm when the voidportion is 3% and increases up to about 650 μΩ.cm when the void portionis 40%.

The coating is disposed as a thin layer on a substrate suitable as animplant. This substrate may be made of plastics, e.g. polyester,polyamide, polyurethane (PUR), polyethylene (PE),polytetrafluoroethylene (PTFE) or DACRON^(R) or of a metal such asmolybdenum, silver, gold, copper, aluminum, tungsten, nickel, chromium,zirconium, titanium, hafnium, tantalum, niobium, vanadium, iron or themixtures or alloys thereof. The coating formed as a thin layer isapplied preferably onto a rough substrate surface whose roughness ischaracterized by a random distribution of the deviations from the meanlevel and the standard deviation of this distribution ranges from 0 to1500 nm, preferably 40 to 120 nm.

The coating may additionally be coated with at least one further thinlayer selected from the group consisting of one or more oxides,preferably SiO₂, TiO₂, ZrO₂, HfO₂, Al₂ O₃, Y₂ O₂, niobium, molybdenum,tungsten and tantalum oxides.

In a preferred embodiment, an intermediate layer producing adhesivestrength is provided between the substrate and the coating. Thisintermediate layer comprises a metal, preferably chromium, copper,nickel, molybdenum, tantalum, niobium, silver or alloys of these metals, or a semiconductor.

Growth of endogenous cells, which serves particularly for anchoring theimplant but also for inducing the formation of a physiological surface,can be controlled by the composition of the material surface. Thesurface coating can be applied to many different basic materials(substrates), e.g. metals and plastics, having differing geometry. Aspecial advantage of the implants according to the invention isrepresented by the cost-effective production as w ell as the fact thatas a function of the chosen method the coating can also be applied tomaterials which d o not tolerate heating because of their specialstructure.

The coating can be made by means of both the CVD method and the PVDmethod, but especially preferably by the PVD method. In particular, thefollowing process is suited for the production of the implants accordingto the invention: While the metal of group IVA of the periodic table isdeposited onto a substrate suitable as an implant, an oxide, nitride orcarbide compound forms by maintaining a gas atmosphere which contains atleast one of the gases N₂, O₂, CH₄ and/or noble gases. In thisconnection, the condensation of the metal particles on a heatable orcoolable substrate is controlled via the total gas pressure p_(tot), thedeposition rate r, the substrate temperature T_(sub) and by the distance1 existing between metal source and substrate, such that the volumefraction of voids is 2 to 45% by volume, whose sizes range from (0.4nm)³ to (50 nm)³. The production parameters are chosen as follows:

T_(sub) =-5 to 400° C.,

1=0.01 to 1.5 m

the partial pressure ratio of the introduced gases N₂ and O₂ : (P_(N2)/P₀₂)=1 to 2000,

P_(tot) =2×10⁻⁵ hPa-4×10⁻² hPa and

r=0.01 to 60 nanometers/s.

For the production process it is necessary to adjust the productionparameters such that the portion of voids is foreseeable. This can bedone by the following procedure: the following applies to substratetemperatures ranging from preferably 100 to 220° C. and a distance ofthe vapor source to the substrate 1 ranging preferably from 0.5 to 1.2m:

A volume fraction of 34% of voids will be achieved if ##EQU1## and thetotal gas pressure P_(tot) ranges from 0.7×10⁻³ hPa to 2×10⁻² hPa.

A volume fraction of 20% of voids is achieved when a choice is madewithin the range of ##EQU2##

Volume fractions between 20 and 34% may be adjusted by chosing themagnitude K according to the following equation: ##EQU3##

Thus, there is the possibility of producing the desired void portion inthe material according to the invention by adjusting rate r, the totalgas pressure P_(tot) and the distance l.

By analogy, the volume fraction of the voids in the layer can becontrolled for the substrate temperatures ranging from preferably 250 to400° C. and l ranging from preferably 0.5 to 1.2 m as follows: A volumefraction of e.g. 40% of voids will be achieved if ##EQU4## and P_(tot)ranges from 2×10⁻² hPa to 4×10⁻² hPa. If K is chosen within the range of##EQU5## the volume fraction of the voids will be 20%. In order torealize values between 20 and 40% of volume fractions, K has to bechosen according to the equation: ##EQU6##

Volume fractions therebetween can be determined by linear interpolationin each case. Small volume fractions of voids (2-20%) are achieved withsmall rates of 0.01-0.1 nm/s and at low gas pressures of 10⁻⁴ -2×10⁻⁴mBar. Very large void portions (>40%) are achieved at high total gaspressures of >4×10⁻² mbar: At these gas pressures, the material may bepresent as a loose compound. The coating is effected on a substratewhich is suited as an implant as defined above.

In the case of plastic implants T_(sub) must, of course, be chosen suchthat plastics do not change, i.e. T_(sub) should be preferably 5 to 20Kelvin below the transformation temperature of the plastics.

The coating is deposited on the substrate in a usual vacuum depositionapparatus as is common to a person skilled in this field.

As compared to the formerly used materials, the advantage of the coatingmaterial of the present invention consists particularly in that it ispossible to vary between differing states (metallic, dielectric). As aresult, the composition of the material can be adjusted such that it mayhave attracting or repelling properties for body cells, blood proteincomponents or microorganisms.

The material has a portion of voids whose volume fraction may beincreased or lowered as desired. By the void portion, the band structurecan be adapted to the demands without changing the chemical composition.Thus, the positive properties of the coating material are lost veryrapidly when the void size is above (50 nm)³. In addition, the growth oradhering of living cells can be increased or decreased by thewell-calculated selection of the void portion. In this connection, it ispreferred that in addition to the above-described voids ranging from(0.4 nm)³ to (50 nm)³ the coating also contains greater voids above (500nm)³. This supports the growth of the implant in given cell structuresor also the growth of cells onto the coated surface. This is supportedby the fact that the implant material to be coated (i.e. the substrate)may have a rough surface. The surface roughness is preferably between0-1500 μm.

Another advantage is that the material can be supplied with depotsubstances, preferably coagulation-inhibiting substances or antibiotics,which are then continuously released from the material.

The surface coating of the implant according to the invention isespecially advantageous because the described material has aconductivity which prevents the formation of volume charges activatingfibrinogen. In addition, the described coating material has an electrondensity which does not permit a space current from fibrinogen to theimplant. This property also prevents the activation of fibrinogen. Thesepositive properties of the described material are adjusted in two ways:on the one hand, by varying the voids within the claimed range and, onthe other hand, by varying the chemical composition. Both possibilitiesserve for achieving that the electron density of the coating is on theenergetic level of the protein states in the blood. In addition, it isbeneficial that the coating be developed in such a way that the chargeexchange processes occurring between the coagulation-specific proteinsand the implant surface are prevented.

The implant can be used for implantation or short-term or long-termintroduction into or attachment to the animal or human body.

The invention is now described in more detail with reference to thefigures:

FIG. 1 shows a section through the coating of an implant

FIG. 2 shows UPS spectra of six coatings of endotracheal tubes

FIG. 3 shows contact angle pictures of 3 modifications of TiN_(x) O_(y)(wherein x=1.0 and y=1.1, but the void portions vary) relative to water.In (a), the void portion is 40%, in (b), it is 22%, and in (c), it is3%. The adhesive properties are controlled by the void portion.

The invention is now described in more detail with reference to theexamples:

EXAMPLES Example 1

The surface of a heart valve prosthesis made of the basic materialtitanium was coated with a coating of TiN_(x) O_(y) (x=1.2 and y=0.6;measured by means of Elastic Recoil Detection (ERD)). The coating wasproduced by means of reactive evaporation with selection of thefollowing parameters: substrate temperature=250° C., distance betweenevaporator and substrate=45 cm; partial pressure ratio (N₂ to O₂)=1500;total pressure=7×10⁻⁴ hPa; deposition rate=0.2 nm/s.

The void portion in the coating material was around 28% and the voidsize was between (0.6 nm)³ and (0.9 nm)³.

FIG. 1 shows a section through the coated heart valve prosthesis, (1)representing the surface of the basic material and (2) denoting thecoating. The coating (2) has a thickness of 3 μm.

Example 2

Six endotracheal tubes were coated. The coating was produced by means ofreactive evaporation with selection of the following parameters:substrate temperature=250° C., distance between evaporator (metalsource) and substrate 45 cm; total pressure=7×10⁻⁴ hPa; depositionrate=0.2 nm/s. The partial pressure ratio (N₂ to O₂) of the supplied gases was varied.

The void portion in the coating material was around 24%, and the voidsize was between (0.6 nm)³ and (0.9 nm)³.

UPS spectra which are shown in FIG. 2 were made of the six coatings.

Graph (1): Coating of TiN_(x) O_(y) wherein x=0.5 and y=1.4, measured bymeans of Elastic Recoil Detection (ERD). The partial pressure ratio (N₂to O₂) was 120.

Graph (2): Coating of TiN_(x) O_(y) wherein x=0.9 and y=1.2, measured bymeans of Elastic Recoil Detection (ERD). The partial pressure ratio (N₂to O₂) was 500.

Graph (3): Coating of TiN_(x) O_(y) wherein x=0.9 and y=0.8, measured bymeans of Elastic Recoil Detection (ERD). The partial pressure ratio (N₂to O₂) was 900.

Graph (4): Coating of TiN_(x) O_(y) wherein x=0.9 and y=0.2, measured bymeans of Elastic Recoil Detection (ERD) The partial pressure ratio (N₂to O₂) was 1200.

Graph (5): Coating of TiN_(x) O_(y) wherein x=1.4 and y=0.3, measured bymeans of Elastic Recoil Detection (ERD) The partial pressure ratio (N₂to O₂) was 1600.

Graph (6): Coating of TiN_(x) O_(y) wherein x=1.5 and y=0.15, measuredby means of Elastic Recoil Detection (ERD) The partial pressure ratio(N₂ to O₂) was 2000.

The coatings on which graphs (2) to (6) are based markedly show a Fermilevel which is correlated with conductivity.

Example 3

Three differing coating materials of TiN_(x) O_(y) (x=1.0, y=1.1) wereapplied by means of vacuum deposition onto endotracheal tubes andcontact angle pictures of the three coatings were made. The results areshown in FIG. 3. (a) is the picture of a sample having a 40% voidportion, (b) is that of a sample having a 22% void portion, and (c) isthat of a sample having a 3% void portion.

The parameters chosen for the production of the coating were:

in the sample having 40% of void portion :

distance between metal source and substrate=70 cm

substrate temperature T_(sub) =300° C.

partial pressure ratio (P_(N2) /P_(O2))=1200

deposition rate r=0.01 nm/s

total gas pressure=2×10⁻² hPa

A void size between (0.8 nm)³ and (2.8 nm)³ resulted.

in the sample having a void portion of 22%:

distance between metal source and substrate=70 cm

substrate temperature T_(sub) =300° C.

partial pressure ratio (P_(N2) /P_(O2))=1200

deposition rate r=0.25 nm/s

total gas pressure=2×10⁻⁴ hPa

A void size between (0.6 nm)³ and (0.9 nm)³ resulted.

in the sample having a void portion of 3%:

distance between metal source and substrate=70 cm

substrate temperature T_(sub) =300° C.

partial pressure ratio (P_(N2) /P_(O2))=1200

deposition rate r=0.7 nm/s

total gas press=2×10⁻⁴ hPa

A void size between (0.4 nm)³ and (0.8 nm)³ resulted.

As follows from FIG. 3, the adhesive properties of the coating can becontrolled by varying the void portion.

What is claimed is:
 1. An implant, comprising a substrate coated with athin layer of a coating material, wherein said coating materialcomprises one or more metals (M) of group IV A of the periodic table,nitrogen (N) and oxygen (O), and wherein 2 to 45% of the volume in thecoating material is formed by voids whose sizes range from (0.4 nm)³ to(50 nm)³ and the remaining volume comprises a composition of a metal ofgroup IV A of the periodic table, nitrogen and oxygen in a ratio of1:(0.1 to 1.7):(0.1 to 1.7), such that a material having the formulaMN_(x) O_(y) wherein x,y=0.1-1.7 results.
 2. The implant according toclaim 1, wherein the coating material further comprises one or more ofthe following chemical compounds:MN_(x) wherein x=0.7 to 1.2 MO_(x)wherein x=0.7 to 1.2 Magnelli phases of the M--O system (M_(n) O_(2n-1))MO₂ M₂ N wherein M is a metal of group IV A of the periodic table. 3.The implant according to any one of claims 1 to 2, wherein the coatingmaterial contains small amounts of carbon compounds of a metal of groupIV A of the periodic table.
 4. The implant according to any one of claim1 or 2, wherein the metals (M) of group IV A of the periodic table,nitrogen (N) and oxygen (O) may occur in the coating material incrystalline or amorphous form.
 5. The implant according to any one ofclaim 1 or 2, wherein the real part of the refractive index of thecoating material for the X-ray wavelength of 0.0709 nm ranges from0.9999984 to 0.9999973.
 6. The implant according to any one of claim 1or 2, wherein the mass density of the coating material ranges from 3.5to 5.4 g/cm³.
 7. The implant according to any one of claim 1 or 2,further comprising at least one compound selected from the groupconsisting of niobium, tantalum, tungsten, molybdenum and alloysthereof.
 8. The implant according to any of claim 1 or 2, wherein thecoating material further comprises hydrogen.
 9. The implant according toany one of claim 1 or 2, wherein the layer thickness of the coatingmaterial on the substrate ranges from 3 nm to 3 mm.
 10. The implantaccording to any one of claim 1 or 2, wherein the specific resistanceranges from 30 to 300000 μΩcm.
 11. The implant according to any of claim1 or 1, wherein the coating material is applied as a thin layer onto arough substrate surface wherein the roughness is characterized by arandom distribution of deviations from a mean level wherein a standarddeviation of the distribution ranges from 0 to 1500 μm.
 12. The implantaccording to any one of claim 1 or 2, wherein the thin coating layer iscoated with at least one further thin layer comprising one or moreoxides selected from the group consisting of SiO₂, TiO₂, ZrO₂, HfO₂, Al₂O₃ Y₂ O₃ , niobium oxide molybdenum oxide, tungsten oxide and tantalumoxide.
 13. The implant according to any one of claim 1 or 2, wherein atleast one further thin layer, made of a metal or a semi-conductor isintroduced between the substrate and the coating.
 14. The implantaccording to any one of claim 1 or 2, wherein the coating material isapplied onto a metallic substrate comprising molybdenum, silver, gold,copper, aluminum, tungsten, nickel, chromium, zirconium, titanium,hafnium, tantalum, niobium, vanadium, iron and one or more alloysthereof.
 15. The implant according to any one of claim 1 or 2, whereinthe coating material is applied onto a plastics substrate comprising apolyester, a polyamide, a polyurethane (PUR), a polyethylene (PE), apolytetrafluoroethylene (PTFE) or DACRON^(R).
 16. The implant accordingto any one of claim 1 or 2, wherein the voids range from (0.4 nm)³ to(50 nm)³ and the coating material has voids greater than (500 nm)³.